My interest in research dates back to high school when my father was diagnosed with pancreatic cancer. Lack of knowledge about and treatments for this disease led me to cancer research as an undergraduate. During my MD/PhD training, my interests broadened to encompass cell biology and immunology. These interests shaped my decision to pursue a residency in internal medicine and fellowship in oncology. During my fellowship in Dr. Laurie Glimcher's laboratory at the Harvard School of Public Health, I am studying the immunology of and role of commensal microbes in inflammatory bowel disease. My post-doctoral training will prepare me to direct a laboratory that studies the function of inflammation and microbes in colon cancer. We have developed a mouse model of ulcerative colitis (DC) that resembles the human disease. Loss of T-bet in the innate immune system results in spontaneous and communicable UC, in the absence of adaptive immunity (termed TRUC) and increased susceptibility to colitis in immunologically intact hosts. I propose to 1)determine how the innate immune system functions in the development of colonic inflammation, 2)interrogate the complex nature of commensal microbial communities, and 3) understand how T-bet and other genes moderate host-commensal relationships. Aim 1will focus on the role of T-bet and colonic DCs and employs transgenic approaches to prove that the DC is the effector cell necesary and sufficient for colitis in TRUC. Employing both immunologic and biochemical approaches, I will study the cytokine milieu and its transcriptional regulators in the TRUC model. In Aim 2,1 will determine the microbes driving colitis using analysis of 16S rDNA enumerations generated from TRUC and genotype controls. I will use both molecular biology and microbiology approaches to validate my findings. In Aim 3, I will use strain differences in TRUC to identify susceptibility modifying genes in colitis using gene wide scanning, molecular biology, and cell biology methodologies. Inflammatory bowel diseases are devastating illnesses that cause significant morbidity and mortality. We have generated a mouse model of ulcerative colitis that bears a great resemblance to the human disease. Studies of this model will hopefully lead to the identification of new therapies for patients with these diseases.